C3G and Ig-MPGN-treatment standard.

Among the broad spectrum of membranoproliferative glomerulonephritis (MPGN), immunofluorescence distinguishes C3 glomerulopathy (C3G), with predominant C3 deposits, and immunoglobulin-associated MPGN (Ig-MPGN), with combined C3 and Ig. However, there are several intersections between C3G and Ig-MPGN. Primary C3G and Ig-MPGN share the same prevalence of low serum C3 levels and of abnormalities of the alternative pathway of complement, and patients who present a bioptic pattern of Ig-MPGN at onset may show a C3G pattern in a subsequent biopsy. There is no specific therapy for primary C3G and Ig-MPGN and prognosis is unfavourable. The only recommended indications are inhibitors of the renin-angiotensin system, lipid-lowering agents and other renoprotective agents. The other drugs used currently, such as corticosteroids and mycophenolate mofetil, are often ineffective. The anti-C5 monoclonal antibody eculizumab has been tested in several patients, with mixed results. One reason for the uncertainty is the extremely variable clinical course, most likely reflecting a heterogeneous pathogenesis. An unsupervised clustering analysis that included histologic, biochemical, genetic and clinical data available at onset in patients with primary C3G and Ig-MPGN identified four clusters characterized by specific pathogenic mechanisms. This approach may facilitate accurate diagnosis and development of targeted therapies. Several trials are ongoing with drugs targeting different molecules of the complement cascade, however it is important to consider which component of the cascade may be the most appropriate for each patient. We review the current standards of treatment and discuss novel developments in the pathophysiology, diagnosis, outcome prediction and management of C3G and Ig-MPGN.

The case of complement inhibitors.

Severe COVID-19 is characterized by lung and multiorgan inflammation and coagulation in the presence of overactivation of the complement system. Complement is a double edged-sward in SARS-Cov-2 infection. On one hand, it can control the viral infection in milder cases, on the other hand in cases with severe and prolonged infection massive complement activation occurs, which can intensify lung and systemic inflammation and promote a procoagulant and prothrombotic state. Several uncontrolled studies and controlled clinical trials with different complement inhibitors have been performed and others are ongoing. Results are promising in some but negative in others. Further studies are required to elucidate the benefit to risk profile of complement inhibitors in COVID-19 patients at different stages of the disease and to clarify the best targets in the complement cascade.